Cerebral cavernous malformation (CCM) is a hereditary vascular disorder that results in the formation of dilated, leaky capillaries in the central nervous system of affected individuals. Patients with CCM suffer from seizures, migraines, focal neurological deficits, and stroke. Loci for CCM have been mapped to three genes, two of which encode scaffolding proteins that facilitate the localization and activation of the MAPK-kinase- kinase MEKK3 at sites of actin reorganization. This observation suggests the hypothesis that CCM is caused by inappropriate regulation of MEKKS-associated signaling networks. This hypothesis is further supported by the finding that targeted disruption of MEKK3 and its downstream targets, p38 and ERK5 all result in embryonic lethality due to defects in vascular morphogenesis. This proposal will investigate the role of the CCM proteins in the spatial and temporal regulation of MEKK3 and its downstream kinases. An in vitro model of astrocyte-endothelial cell interactions will be used to test the hypothesis that the CCM proteins regulate intercellular signals required for vascular homeostasis in the nervous system. This research will lend insight into the function of scaffolding proteins as coordinators of the spatial and temporal activation of signaling networks and their role in vascular physiology and disease. [unreadable] [unreadable] [unreadable]